Cargando…
Extracellular Nucleosomes Accelerate Microglial Inflammation via C-Type Lectin Receptor 2D and Toll-Like Receptor 9 in mPFC of Mice With Chronic Stress
Damage-associated molecular patterns (DAMPs) are the primary promoter of progressive neuroinflammation and are associated with chronic stress-related emotional disorders. The present study investigated the role and mechanism of extracellular nucleosomes and histones, the newly defined DAMPs, in mice...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9276970/ https://www.ncbi.nlm.nih.gov/pubmed/35844599 http://dx.doi.org/10.3389/fimmu.2022.854202 |
_version_ | 1784745837502398464 |
---|---|
author | Wu, Huanghui Bao, Han Liu, Cong Zhang, Qiao Huang, Ailing Quan, Minxue Li, Chunhui Xiong, Ying Chen, Guozhong Hou, Lichao |
author_facet | Wu, Huanghui Bao, Han Liu, Cong Zhang, Qiao Huang, Ailing Quan, Minxue Li, Chunhui Xiong, Ying Chen, Guozhong Hou, Lichao |
author_sort | Wu, Huanghui |
collection | PubMed |
description | Damage-associated molecular patterns (DAMPs) are the primary promoter of progressive neuroinflammation and are associated with chronic stress-related emotional disorders. The present study investigated the role and mechanism of extracellular nucleosomes and histones, the newly defined DAMPs, in mice with chronic stress. C57BL/6 mice were exposed to chronic unpredictable mild stress (CUMS) and corticosterone drinking, respectively, for 4 weeks. Negative emotional behaviors were comprehensively investigated. Microglial morphology, oxidative stress, and inflammation, as well as C-type lectin receptor 2D (Clec2d) and Toll-like receptor 9 (TLR9) expression in medial prefrontal cortex (mPFC) were assessed with flow cytometer and cell sorting. Specifically, microglial pro-inflammatory activation and inflammation were further investigated with stereotactic injection of recombinant nucleosomes and histones in mPFC and further evaluated with AAV-Clec2d knocking-down, DNase I, and activated protein C (APC) pretreatment. Moreover, the rescue effect by AAV-Clec2d knocking-down was observed in mice with chronic stress. Mice with chronic stress were presented as obviously depressive- and anxiety-like behaviors and accompanied with significant microglial oxidative stress and inflammation, indicating by reactive oxygen species (ROS) production, primed nuclear factor-κB (NF-κB) signaling pathway, activated NACHT, LRR, and PYD domain–containing protein 3 (NLRP3) inflammasome, and upregulated Clec2d and TLR9 in mPFC, together with histones dictation in cerebrospinal fluid and extracellular trap formation. Stereotactic injection of nucleosomes was contributed to promote microglial inflammation rather than histones in mPFC, indicating that the pro-inflammatory role was derived from extracellular histones-bound DNA but not freely histones. AAV-Clec2d knocking-down, DNase I, and APC were all effective to inhibit nucleosome-induced microglial oxidative stress and inflammation. Moreover, AAV-Clec2d knocking-down in mice with chronic stress exhibited reduced microglial inflammation and improved negative emotional behaviors. Our findings reveal a novel mechanism of DAMP-associated inflammation that extracellular nucleosomes accelerate microglial inflammation via Clec2d and TLR9, and then contribute to chronic stress-induced emotional disorders. |
format | Online Article Text |
id | pubmed-9276970 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-92769702022-07-14 Extracellular Nucleosomes Accelerate Microglial Inflammation via C-Type Lectin Receptor 2D and Toll-Like Receptor 9 in mPFC of Mice With Chronic Stress Wu, Huanghui Bao, Han Liu, Cong Zhang, Qiao Huang, Ailing Quan, Minxue Li, Chunhui Xiong, Ying Chen, Guozhong Hou, Lichao Front Immunol Immunology Damage-associated molecular patterns (DAMPs) are the primary promoter of progressive neuroinflammation and are associated with chronic stress-related emotional disorders. The present study investigated the role and mechanism of extracellular nucleosomes and histones, the newly defined DAMPs, in mice with chronic stress. C57BL/6 mice were exposed to chronic unpredictable mild stress (CUMS) and corticosterone drinking, respectively, for 4 weeks. Negative emotional behaviors were comprehensively investigated. Microglial morphology, oxidative stress, and inflammation, as well as C-type lectin receptor 2D (Clec2d) and Toll-like receptor 9 (TLR9) expression in medial prefrontal cortex (mPFC) were assessed with flow cytometer and cell sorting. Specifically, microglial pro-inflammatory activation and inflammation were further investigated with stereotactic injection of recombinant nucleosomes and histones in mPFC and further evaluated with AAV-Clec2d knocking-down, DNase I, and activated protein C (APC) pretreatment. Moreover, the rescue effect by AAV-Clec2d knocking-down was observed in mice with chronic stress. Mice with chronic stress were presented as obviously depressive- and anxiety-like behaviors and accompanied with significant microglial oxidative stress and inflammation, indicating by reactive oxygen species (ROS) production, primed nuclear factor-κB (NF-κB) signaling pathway, activated NACHT, LRR, and PYD domain–containing protein 3 (NLRP3) inflammasome, and upregulated Clec2d and TLR9 in mPFC, together with histones dictation in cerebrospinal fluid and extracellular trap formation. Stereotactic injection of nucleosomes was contributed to promote microglial inflammation rather than histones in mPFC, indicating that the pro-inflammatory role was derived from extracellular histones-bound DNA but not freely histones. AAV-Clec2d knocking-down, DNase I, and APC were all effective to inhibit nucleosome-induced microglial oxidative stress and inflammation. Moreover, AAV-Clec2d knocking-down in mice with chronic stress exhibited reduced microglial inflammation and improved negative emotional behaviors. Our findings reveal a novel mechanism of DAMP-associated inflammation that extracellular nucleosomes accelerate microglial inflammation via Clec2d and TLR9, and then contribute to chronic stress-induced emotional disorders. Frontiers Media S.A. 2022-06-29 /pmc/articles/PMC9276970/ /pubmed/35844599 http://dx.doi.org/10.3389/fimmu.2022.854202 Text en Copyright © 2022 Wu, Bao, Liu, Zhang, Huang, Quan, Li, Xiong, Chen and Hou https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Wu, Huanghui Bao, Han Liu, Cong Zhang, Qiao Huang, Ailing Quan, Minxue Li, Chunhui Xiong, Ying Chen, Guozhong Hou, Lichao Extracellular Nucleosomes Accelerate Microglial Inflammation via C-Type Lectin Receptor 2D and Toll-Like Receptor 9 in mPFC of Mice With Chronic Stress |
title | Extracellular Nucleosomes Accelerate Microglial Inflammation via C-Type Lectin Receptor 2D and Toll-Like Receptor 9 in mPFC of Mice With Chronic Stress |
title_full | Extracellular Nucleosomes Accelerate Microglial Inflammation via C-Type Lectin Receptor 2D and Toll-Like Receptor 9 in mPFC of Mice With Chronic Stress |
title_fullStr | Extracellular Nucleosomes Accelerate Microglial Inflammation via C-Type Lectin Receptor 2D and Toll-Like Receptor 9 in mPFC of Mice With Chronic Stress |
title_full_unstemmed | Extracellular Nucleosomes Accelerate Microglial Inflammation via C-Type Lectin Receptor 2D and Toll-Like Receptor 9 in mPFC of Mice With Chronic Stress |
title_short | Extracellular Nucleosomes Accelerate Microglial Inflammation via C-Type Lectin Receptor 2D and Toll-Like Receptor 9 in mPFC of Mice With Chronic Stress |
title_sort | extracellular nucleosomes accelerate microglial inflammation via c-type lectin receptor 2d and toll-like receptor 9 in mpfc of mice with chronic stress |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9276970/ https://www.ncbi.nlm.nih.gov/pubmed/35844599 http://dx.doi.org/10.3389/fimmu.2022.854202 |
work_keys_str_mv | AT wuhuanghui extracellularnucleosomesacceleratemicroglialinflammationviactypelectinreceptor2dandtolllikereceptor9inmpfcofmicewithchronicstress AT baohan extracellularnucleosomesacceleratemicroglialinflammationviactypelectinreceptor2dandtolllikereceptor9inmpfcofmicewithchronicstress AT liucong extracellularnucleosomesacceleratemicroglialinflammationviactypelectinreceptor2dandtolllikereceptor9inmpfcofmicewithchronicstress AT zhangqiao extracellularnucleosomesacceleratemicroglialinflammationviactypelectinreceptor2dandtolllikereceptor9inmpfcofmicewithchronicstress AT huangailing extracellularnucleosomesacceleratemicroglialinflammationviactypelectinreceptor2dandtolllikereceptor9inmpfcofmicewithchronicstress AT quanminxue extracellularnucleosomesacceleratemicroglialinflammationviactypelectinreceptor2dandtolllikereceptor9inmpfcofmicewithchronicstress AT lichunhui extracellularnucleosomesacceleratemicroglialinflammationviactypelectinreceptor2dandtolllikereceptor9inmpfcofmicewithchronicstress AT xiongying extracellularnucleosomesacceleratemicroglialinflammationviactypelectinreceptor2dandtolllikereceptor9inmpfcofmicewithchronicstress AT chenguozhong extracellularnucleosomesacceleratemicroglialinflammationviactypelectinreceptor2dandtolllikereceptor9inmpfcofmicewithchronicstress AT houlichao extracellularnucleosomesacceleratemicroglialinflammationviactypelectinreceptor2dandtolllikereceptor9inmpfcofmicewithchronicstress |